Muscle wasting is a debilitating feature of many disease states including diabetes and renal failure. We initially identified atrogin-1 as a gene that is strongly induced during muscle wasting in various animal models of disease. Its absence protects muscles from atrophy. In the seven years since its discovery, upregulation of this gene has become a major biomarker defining the atrophy state. Atrogin-1 acts as one component of a ubiquitin-protein ligase that catalyzes the degradation of key proteins, leading to muscle wasting. During the past study period;we made large strides in understanding the signaling pathways that lead to atrogin-1 induction in atrophying muscle. Initially we had believed this gene was only expressed in skeletal and cardiac muscle, and only involved in atrophy of these tissues. Our recent data, however, has shown that atrogin-1 has more diverse cellular functions, playing a critical role in the skeletal muscle toxicity of HMG CoA reductase inhibitors (statins) and in the normal involution of the uterus following delivery. This proposal continues our exploration of atrogin-1 function by studying the pathways that induce atrogin-1 in clinically important physiological and pathological processes. We shall develop models of statin toxicity in cultured muscle cells, zebrafish and mice, and identify the signaling pathways and prenylated protein intermediates involved in atrogin-1 expression. We shall utilize our colony of atrogin-1 knockout mice to study the effects of atrogin-1 absence in the development of statin myopathy. In an effort to understand how atrogin-1 promotes protein breakdown and muscle damage, we will identify its role in the nucleus during atrophy. Elucidating the functions of atrogin-1 will help characterize the mechanisms and physiological regulation of muscle protein breakdown and may also allow the development of pharmacological inhibitors that could combat muscle wasting conditions and their associated morbidity. PUBLIC HEALTH RELEVANCE: Atrogin-1 is part of a complex that triggers the destruction of muscle proteins, and its activation leads to muscle wasting. Our new data suggests that atrogin-1 has broader functions, playing a critical role in the toxicity of cholesterol-lowering medications (statins). This proposal continues our exploration of atrogin-1 function by studying the pathways that activate atrogin-1 in these conditions. These studies of atrogin-1 function will help elucidate how the body regulates muscle size, and will ultimately lead to development of drugs to combat muscle wasting.